Contemporary Western type diets challenge lipid and glucose homeostasis by overloading blood with cholesterol, triglycerides, and glucose. Their excess has serious consequences for the cardiovascular system (atherosclerosis) and liver (steatohepatitis), and contributes to the metabolic syndrome, a leading cause of mortality worldwide. Disordered lipid and glucose metabolism elicits an inflammatory response (metabolic inflammation) by signaling to the nucleus through the nuclear transport of stress-responsive transcription factors (SRTFs). They reprogram immune and non-immune cells into an inflammatory phenotype. Lipid homeostasis comprises a tightly regulated physiologic balance between dietary lipid intake, endogenous production, and intestinal disposal. Derangement of lipid homeostasis is linked to excessive signaling to the nucleus by sterol regulatory element-binding proteins (SREBPs) 1a, 1c, and 2 (Horton, J. D., Goldstein, J. L., and Brown, M. S. (2002) J Clin Invest 109, 1125-11314-8); Ferre, P., and Foufelle, F. (2007) Horm Res 68, 72-82; Raghow, R., Yellaturu, C., Deng, X., Park, E. A., and Elam, M. B. (2008) Trends Endocrin Met 19, 65-73; Jeon, T. I., and Osborne, T. F. (2012) Trends Endocrin Met 23, 65-72). SREBPs are transcription factors with a basic helix-loop helix leucine zipper (bHLH-Zip) domain. They are sequestered in the membrane of the endoplasmic reticulum (ER) in a complex with the sterol sensor and transporter SREBP cleavage-activating protein (Scap), which regulates their subsequent transit from the ER to the Golgi apparatus. There, two membrane proteases process SREBPs to release a ˜60 kDa NH2-terminal segment termed nuclear SREBP (nSREBP), that contains the bHLH-Zip region. As nSREBPs lack a classic nuclear localization sequence (NLS), their shuttling to the nucleus is provided solely by a unique association with importin beta rather than first being complexed with one of the importins/karyopherins alpha that utilize importin beta for docking to the nuclear pore (Lee, S. J., Sekimoto, T., Yamashita, E., Nagoshi, E., Nakagawa, A., Imamoto, N., Yoshimura, M., Sakai, H., Chong, K. T., Tsukihara, T., and Yoneda, Y. (2003)). Science 302, 1571-15759). Importin beta-mediated nuclear translocation of SREBPs culminates in activation of a set of genes that encode proteins involved in synthesis of cholesterol and its cellular binding pathways and in fatty acid, triglyceride, and phospholipid synthetic pathways (Horton, J. D., Goldstein, J. L., and Brown, M. S. (2002) J Clin Invest 109, 1125-11314-8). Moreover, carbohydrate response element binding protein (ChREBP) is a glucose-activated transcription factor involved in the development of metabolic syndrome (Iizuka, K., and Horikawa, Y. (2008) Endocrine journal 55, 617-624). ChREBP belongs to the same bHLH-Zip family as SREBPs and in response to elevated blood glucose regulates expression of genes involved in glycolysis, lipogenesis, and gluconeogenesis that convert excess carbohydrates into liver triglycerides rather than glycogen. Though ChREBP is a bHLH-Zip domain transcription factor in the same family as SREBPs, it also contains a classic NLS recognized by importins alpha (Ge, Q., Nakagawa, T., Wynn, R. M., Chook, Y. M., Miller, B. C., and Uyeda, K. (2011) J Biol Chem 286, 28119-28127).
The autoregulatory loop of cholesterol and fatty acid synthesis is disrupted by genetic defects in LDL receptor (LDLR) function that increase the risk of early heart attack by more than 10-fold in heterozygous familial hypercholesterolemia. Compounding hyperlipidemia, the inflammatory response enhances atherosclerosis development. This process depends on the prominent role of macrophages as well as T and B lymphocytes, and other cells of the immune system. Overabundant cholesterol-carrying low-density lipoproteins that saturate the blood vessel wall at zones of hemodynamic stress and formation of cholesterol crystals evoke an inflammatory response mediated by the NLRP3 inflammasome, generating mature proinflammatory cytokines interleukin-1β (IL-1β) and interleukin 18 (IL-18).
These and many other mediators that participate in the atherosclerosis-promoting inflammatory process are regulated by nuclear factor-kappa B (NF-κB) and other SRTFs, such as AP-1, NFAT, and STAT1. SRTFs are widely distributed in the vascular and immune cells that gather in atherosclerotic lesions (Hansson, G. K. & Hermansson, A., Nat Immunol 12 (3), 204-212 (2011); Brand, K. et al., J. Clin. Invest. 97 (7), 1715-1722 (1996)). SRTFs are transported to the nucleus in response to proinflammatory stimuli, including Western type diet-induced hyperlipidemia, recognized by innate immunity Toll-like receptors, adaptive immunity T and B cell antigen receptors, and cytokine receptors. In the nucleus, SRTFs activate genes that encode mediators of inflammation. Autoimmune responses to LDL play a significant role in the development of atherosclerosis.
There is an urgent need for therapeutics that can arrest Western diet-type-driven hyperlipidemia, fatty liver, atherosclerosis, Type 2 diabetes, and obesity, and prevent complications associated with such disorders (e.g., several cardiovascular, hepatobiliary, and renal complications).